Amgen Inc., Thousand Oaks, CA 91320, USA.
Clin Exp Immunol. 2011 Jan;163(1):77-87. doi: 10.1111/j.1365-2249.2010.04259.x. Epub 2010 Nov 16.
B and T lymphocyte attenuator (BTLA) is an immunoglobulin superfamily member surface protein expressed on B and T cells. Its ligand, herpesvirus entry mediator (HVEM), is believed to act as a monomeric agonist that signals via the CRD1 of HVEM to inhibit lymphocyte activation: HVEM is also the receptor for lymphotoxin-α and LIGHT, which both bind in the CRD2 and CRD3 domains of the HVEM molecule, and for CD160 which competes with BTLA. We have shown that recombinant HVEM and a panel of different monoclonal antibodies specifically bind murine BTLA on both B and T cells and that some antibodies inhibit anti-CD3ε-induced T cell proliferation in vitro, but only when constrained appropriately with a putatively cross-linking reagent. The antibodies had no significant effect on in vitro T cell proliferation in a mixed lymphocyte reaction (MLR) assay nor on in vitro DO11.10 antigen-induced T cell proliferation. None of these antibodies, nor HVEM-Fc, had any significant effect on in vitro B cell proliferation induced by anti-immunoglobulin M antibodies (±anti-CD40) or lipopolysaccharide. We further elucidated the requirements for inhibition of in vitro T cell proliferation using a beads-based system to demonstrate that the antibodies that inhibited T cell proliferation in vitro were required to be presented to the T cell in a cis, and not trans, format relative to the anti-CD3ε stimulus. We also found that antibodies that inhibited T cell proliferation in vitro had no significant effect on the antibody captured interleukin-2 associated with the in vivo activation of DO11.10 T cells transferred to syngeneic recipient BALB/c mice. These data suggest that there may be specific structural requirements for the BTLA molecule to exert its effect on lymphocyte activation and proliferation.
B 和 T 淋巴细胞衰减器（BTLA）是一种免疫球蛋白超家族成员表面蛋白，表达于 B 和 T 细胞上。其配体，疱疹病毒进入介体（HVEM），被认为是一种单体激动剂，通过 HVEM 的 CRD1 信号传导，抑制淋巴细胞激活：HVEM 也是淋巴毒素-α和 LIGHT 的受体，它们都结合在 HVEM 分子的 CRD2 和 CRD3 结构域，以及与 BTLA 竞争的 CD160。我们已经表明，重组 HVEM 和一组不同的单克隆抗体特异性结合小鼠 B 和 T 细胞上的 BTLA，并且一些抗体在体外抑制抗-CD3ε诱导的 T 细胞增殖，但只有在适当的与推测交联试剂约束时才会发生。这些抗体在体外混合淋巴细胞反应（MLR）测定中对 T 细胞增殖没有显著影响，也没有对体外 DO11.10 抗原诱导的 T 细胞增殖产生影响。这些抗体或 HVEM-Fc 都没有对体外抗免疫球蛋白 M 抗体（±抗-CD40）或脂多糖诱导的 B 细胞增殖产生任何显著影响。我们进一步阐明了使用基于珠子的系统抑制体外 T 细胞增殖的要求，证明在体外抑制 T 细胞增殖的抗体需要在 cis 而不是 trans 格式相对于抗-CD3ε刺激呈现给 T 细胞。我们还发现，在体外抑制 T 细胞增殖的抗体对体内激活的 DO11.10 T 细胞转移到同基因受体 BALB/c 小鼠时与抗体捕获的白细胞介素-2 没有显著影响。这些数据表明，BTLA 分子可能需要特定的结构要求来发挥其对淋巴细胞激活和增殖的作用。
